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As specialists seek better, more effective treatments for bipolar disorder, a key question remains: Do genetics or life experiences play a bigger role in its development?

Join us as we speak with Dr. Francis McMahon of the National Institute of Mental Health about research on genetics and bipolar disorder, including a gene study that Dr. McMahon is working on now. You'll also hear about evidence pointing to a higher incidence of bipolar disorder among certain families, as well as research into emotional trauma, like the loss of a parent, as a risk factor. Plus, we'll discuss potential treatment advances that could result from a better understanding of the causes of bipolar disorder.

As always, our expert guests answer questions from the audience.

Announcer:

Welcome to this HealthTalk webcast. Before we begin, we remind you that the opinions expressed on this webcast are solely the views of our guests. They are not necessarily the views of HealthTalk, our sponsors or any outside organization. And, as always, please consult your own physician for the medical advice most appropriate for you.

Now here's your host.

Patricia Murphy:

Since the beginning of the human genome project, researchers have accelerated their search for links between genes and illnesses. When it comes to bipolar disorder, just how much progress have they made? Hello and welcome to this HealthTalk webcast, Causes of Bipolar Disorder: Nature or Nurture? I'm your host, Patricia Murphy.

Joining us on the phone from Bethesda, Maryland is Dr. Francis McMahon, chief of the genetic basis of mood and anxiety disorders program at the National Institutes of Mental Health, where he researches genetic variations that play a role in mood and anxiety disorders such as bipolar disorder. Welcome to HealthTalk, Dr. McMahon.

Dr. Francis McMahon:

Thanks for having me.

Patricia:

Dr. McMahon, many of us have an idea about genes and what they do inside our bodies. But if we had to explain it, we might run into trouble. Would you describe what genes are and how they work?

Dr. McMahon:

Well, genes are kind of one of the blueprints of the way our biology works. They are strings of information that tell the body how to build molecules that are important in growth, metabolism and signaling, primarily proteins, which are the building blocks of tissues ranging from your heart to your liver to your blood to your brain, but also we are learning increasingly that genes also encode other kinds of molecules whose job seems to be to regulate the turning on and off of other genes.

Patricia:

And why is it important to discover these genetic links to bipolar disorder?

Dr. McMahon:

Well, we have known for a long time that bipolar disorder is primarily genetic. This is information that goes back close to a hundred years. Early twin studies, almost as early as the concept of bipolar disorder itself, showing that identical twins, who on average share all of their genes, are much more likely to have the illness when one of their co-twins does than fraternal twins or non-identical twins who on average share only about 50 percent of their genes. And, in fact, based on the data that's been gleaned over many of these studies over many years, scientists estimate that about 80 percent of the individual risk for bipolar disorder is genetically determined. Now, when we put that against how little we really understand about the underlying biology of this illness or what goes wrong in the brain when someone has bipolar disorder, the idea of studying the genes is that they might actually give us an indirect window into that biology.

Patricia:

And what have we learned about that biology?

Dr. McMahon:

Well, we have learned it's very complex. By attempting to study the biology directly, neuroscientists have been able to find a variety of things that seem to be different in the brains of people with bipolar disorder: the way in which emotions are processed, the way in which information in general is processed, certain structures of the brain that are a little bit smaller or a little bit larger in some people with bipolar disorder, ways in which the body's stress mechanisms work that seem to be different in some people with bipolar disorder. But it all doesn't add up to a very clear-cut picture. And so the thinking now is that what we call bipolar disorder may very well be a collection of distinct diseases that share in common this clinical experience of depression on the one hand and mania on the other, but when we look at the brain level the biological causes may be very variable.

The analogy might be something like a heart attack or even just chest pains that when someone experiences severe chest pains that might reflect underlying heart disease, it might reflect severe indigestion, it might reflect cancer of the esophagus, it might reflect pneumonia or some other infection of the lungs. And without any way to really sort out the underlying biology, we have no hope of really untangling the causes.

In the case of bipolar disorder, we are probably a little bit beyond the level of just chest pain but not a whole lot. We still rely very heavily upon our patients to tell us how they are feeling and how they are thinking, on their families to tell us how they are behaving. And there are no blood tests, there are no imaging studies, there are no electroencephalograms that can be done that will diagnose bipolar disorder.

Patricia:

Right. From what we know now, it sounds like we are a long way from actually developing new treatments. Are we 10 years out? Are we 15 years out?

Dr. McMahon:

Well, new treatments come from lots of different sources. And if you were to say how far out are we from developing new treatments based on genetic discoveries, I would say it probably is something we can measure in years. But I would hasten to add that new treatments are coming down the pike all the time from a variety of sources. Just last year, one of my colleagues here at the National Institutes of Health did a study of an existing medication known as ketamine, which a variety of neurobiological series suggested might be helpful as a rapid treatment for depression without any supporting information from genetics at this point, and found indeed that in a small sample of people with treatment-resistant depression that the ketamine was enormously effective. So we expect that new treatments and new drugs might come up unpredictably, sometimes even serendipitously from a variety of sources, although the new drugs based on genetic discoveries might still be a few years off.

Patricia:

How do researchers study genes? What methods do you use?

Dr. McMahon:

Well, until the last couple of years, the primary approaches have been what are called genetic linkage studies and candidate gene studies. Genetic linkage studies are the kinds of studies where large families are asked to participate, usually families where several people have an illness, and genetic markers are used to track the chromosomes as they are transmitted from parents to offspring in those families. The genetic markers allow us to actually see which portions of which chromosomes tend to be inherited along with the illness within a family. And if that same pattern is seen over and over again in different families, that can help us identify which chromosomal region is likely to harbor a gene that's important in the disease.

Now, the problem with linkage studies is that they don't really pinpoint a particular gene. The chromosomal region might be quite large. It might contain dozens or even hundreds of genes. The other thing about linkage studies is that they only work well when there are one or a few genes that play a major role in causing the illness. So, for example, diseases like Huntington disease, cystic fibrosis and some rare forms of Alzheimer's disease have worked well in genetic linkage studies, and we have identified very clear-cut disease predisposing mutations for all of those diseases using linkage methods. In the case of more common illnesses like bipolar disorder, we think that there are probably several genes that each play a small role, and in that circumstance linkage studies don't work well.

Patricia:

Okay. Oh, go ahead.

Dr. McMahon:

So the message that is now becoming the standard approach is what's called a genetic association study. And in this approach, we use genetic markers to actually look for a direct relationship between the prevalence of the illness in a population and prevalence of a marker in that same population. That method seems to work better for common diseases because it doesn't depend on there being only one or two important genes. On the other hand, it requires that sometimes very large populations be studied. The best successes for this approach so far have been diseases like type II diabetes, where tens of thousands of individuals have been studied.

It's also important for these kinds of studies to use lots of markers, preferably several markers in every gene and also lots of markers in between genes, regions that might play an important role in regulating genes. And so up until the last year or two, this was not technologically feasible, but new advances using DNA microchip technology have now made this not only feasible but actually quite routine. Although the studies are still rather expensive, they can be accomplished relatively quickly and very accurately using the latest technology.

Patricia:

And what about gene mapping, what is gene mapping?

Dr. McMahon:

Well, gene mapping is the general term applied to all of these methods, the idea being to try and pinpoint genes that play a role in illness. The emphasis on mapping was created in the age of linkage analysis, which really sort of envisioned the chromosomes as little road maps and linkage findings as ways of narrowing down the address. We used to say that if we think of the whole genome, all 23 pairs of chromosomes as the entire planet, the linkage finding might allow you to narrow things down to a city and occasionally to a county. But in the current era of genome-wide association studies, we actually get a complete picture of the entire genome in a single experiment. The positions of those markers are already known. They are selected because they map to a very particular place in the genome, and so the association and the location are almost synonymous.

I use the word "almost" because we are learning that genetic variation doesn't always affect the gene in which the variation occurs, that gene regulation, the turning on and off of genes can sometimes be explained by variations that are quite far away from the genes that are being regulated, and this is a brand-new field of research in human genetics that is bringing out new surprises almost every week.

Patricia:

Wow. Now, some researchers have discovered that there are genetic deletions, duplications and variations in genes that are related to mental illness. Can you tell us more about that?

Dr. McMahon:

Yes. And that's a whole other approach distinct from genetic linkage and somewhat different from genome-wide association studies. In the deletions and duplications, what we are looking for actually are structural differences in chromosomes, in the number of copies of chromosomal segments that may contain one or more genes. We used to think that by far the rule was that we each inherit one copy of each chromosome from each of our parents, one from our mother and one from our father, and that we have exactly two functioning copies of each gene. There are some complications with the X chromosome which I won't go into, but that was considered the basic dogma of genetics until quite recently.

But it then became clear as we started to have these genome-wide sets of data that there were these regions that looked mysteriously different from individual to individual. And when we used molecular methods to figure out what the differences were, it turned out to many people's surprise that they were segments of chromosomes that were either duplicated, that is present in more than two copies, or deleted, present in only one or no copies in an individual. Now, even more surprising was that we found that this kind of variation is widespread in the entire human genome, and we all carry many of these deletions and duplications. It also seems that in most cases they have no impact, at least nothing that we can measure at the clinical level.

But the reason these kinds of variations have caused such excitement is it seems that in some cases that may be rare, they do contribute to disease. In the last couple of months, there have been several studies that have come out showing suggestive evidence that these kinds of rare duplications and deletions may play a role in diseases like autism and schizophrenia in addition to the long-standing role they have been known to play in a variety of other developmental disorders.

Patricia:

And do imaging technologies like MRIs and CAT scans help researchers like yourself understand genes and how they work in the brain and how they are linked to bipolar disorder?

Dr. McMahon:

Imaging methods can be very helpful in this way. And we are only now discovering ways in which we can get genetic data and imaging data to work together to tell a complete story. Now, just a few years ago, people who worked in the imaging field and people who worked in the genetics field almost never talked. We had very distinct vocabularies, very distinct ways of approaching similar problems, and we had a very hard time understanding how we thought about these disorders. But just in the last couple of years, increasingly, imagers and genetic researchers have gotten together, and we've realized that imaging technology can be helpful in a variety of ways.

One way it can be helpful is to actually sort out distinct groups of individuals who have similar clinical illnesses. For example, people with bipolar disorder sometimes have a particular kind of finding on MRI imaging called unidentified bright objects. And on an MRI they look just like a white spot that is often seen in the gray matter of the brain, in the deep part of the brain, and these are common findings in the MRI images of older people, but they are rarely seen in people before the age of 50 unless those people have bipolar disorder. Not everybody with bipolar disorder has these, but it's been widely thought that the people with bipolar disorder who do have these unidentified bright objects might actually represent a distinct entity. And we could use that information then to try to come up with a more defined group of people with the illness whose genetic commonalities could then be more informative.

Patricia:

Well, that all sounds very hopeful. What are you working on at the National Institutes of Mental Health these days?

Dr. McMahon:

Well, my group is focused on understanding how genes contribute to the risk for both mood and anxiety disorders. So we study bipolar disorder, we study major depressive disorder, and we also study panic disorder, which is a very common anxiety disorder. And we are using most of the methods that I have talked about so far today to try to narrow down the focus on a few key genes whose biology we can then study and understand. What we are finding though is that for all of these disorders that there are really many genes that contribute each a little bit to individual risk for disease. And so it's proven to be quite a complex and challenging problem to put these together into a coherent biological story.

Patricia:

What are you hoping to be able to do?

Dr. McMahon:

Well, ultimately we would really like to come up with better ways both to diagnose and treat these illnesses. As I said earlier, diagnosis right now is based primarily on clinical history and on criteria that were put together by groups of experts but without any real assurance that people who have the same diagnosis share the same underlying disease. We are hoping that with genetic findings we will be able to sort out individuals who have a shared biology. That's important because then we can understand better what's going wrong in the brain but also maybe come up with better ways to target individual treatments to individual patients.

Patricia:

Right.

Dr. McMahon:

Treatments that are available now for illnesses like bipolar disorder are very helpful for some people and not helpful at all for others. And we have no understanding about why that is. Lithium, for example, which has been used for bipolar disorder for close to 40 years, can be a miracle drug for about 20 or 30 percent of people with bipolar disorder, and it's totally useless for about 10 or 20 percent of people. We don't understand why that should be, and these are the kinds of things that we are hoping that genetic discoveries will help us understand.

Patricia:

Dr. McMahon, what is a genetic vulnerability to bipolar disorder?

Dr. McMahon:

Well, as I mentioned earlier, diseases like bipolar disorder can't really be explained by a single gene. Although they are considered to be about 80 percent heritable, that doesn't guarantee that a single gene is involved. In fact, our best information is that many genes are each contributing. So many people may carry genetic risk factors for bipolar disorder but never develop the illness. And that's what we mean by vulnerability, that not everybody who carries the genetic variances that increase risk also develop the illness.

A good analogy there comes from, say, cardiovascular disease where we know things like high blood pressure, high cholesterol, smoking and other lifestyle factors each contribute to the risk for cardiovascular disease but that there are plenty of people who walk around with high blood pressure or high cholesterol, etc., and they never develop a heart attack. So we think of these as vulnerabilities bearing a statistical or probabilistic relationship to disease rather than a deterministic relationship.

Another analogy I like to use is that you can imagine an automobile accident occurring at a busy intersection during rush hour on a given day, and when the investigators come in to figure out what caused the accident, they find that the street was slick, the signal wasn't functioning properly, one of the people involved in the accident was driving a bit fast, the other one might have been talking on his cell phone and not paying close attention, maybe there was drinking involved. And if you were to say to the investigators, "Well, what one thing caused this accident?" They probably couldn't tell you that because all of these things contributed to the probability that an accident would occur. On the other hand, an important thing that that analogy teaches us though is that if any one of those causative factors were removed, the accident might not occur. So although we think of bipolar disorder as being related to many genes, that doesn't mean that we need to understand how each gene works or that we need to fix each gene in order to be able to relieve symptoms of the illness or maybe even prevent the illness in individuals.

Patricia:

Which leads me to my next question which is do you consider genes linked to bipolar disorder to be defective?

Dr. McMahon:

I think it's hard to know for sure how this will all play out, but I think what we are going to find is that there probably are some genes that would meet the definition of defective, meaning that they carry a major mutation that leads to a loss of function of the protein or are completely deleted and so that they are not producing any protein at all, and that these are major risk factors in certain individuals and certain families, but that the majority of bipolar disorder will probably be related to much more common forms of what we can best think of as genetic variation, and that maybe when several of these forms of variation come together in the right person at the right time with the right life history, then the illness occurs.

Patricia:

Have you been able to link malfunctioning genes to symptoms of bipolar disorder?

Dr. McMahon:

So far, the best evidence we have points to a variety of common genes that are more common in people with the illness. We carried out a study last year that looked at about 550,000 markers spread throughout all human genes. And we looked at two large groups of people with bipolar disorder, one put together here in the United States as part of the NIMH genetics initiative and another put together by a group of researchers in Germany. Now, when we looked for differences in the forms of these genes between people with the illness and people without the illness, we found that there were 80 different genes that contained differences that we could detect both in the NIMH sample and in the German sample. Subsequent studies carried out in England and also here in the United States have found additional genes that seem to play a role, and only some of them overlap with the genes that we found. So it's looking like we have a large group of genes that play a role.

And one of the things that was interesting about the genes that we found was that many of them seemed to be involved in some of the same cellular processes that lithium is known to interact with. Some of the other genes that have been reported recently also seemed to play a role in ion channels, which are important in determining when brain cells will fire, when they will activate, and that seems to be also an important part of the underlying biology.

Patricia:

Can a malfunctioning gene be repaired or turned off?

Dr. McMahon:

In theory it can, but in practice it's very hard to do. It's also quite hard to do when you are talking about a gene in the brain.

Patricia:

Why?

Dr. McMahon:

So the brain occupies a very privileged place in the body within what's called the blood-brain barrier, which is quite a powerful barrier to biological agents entering the brain from the bloodstream. So even when we develop medications to treat psychiatric or neurological diseases, one of great challenges in developing effective medications is to find those that will effectively pass through the blood-brain barrier. So what we are thinking in terms of how we can use genetic findings for treatment of illnesses like bipolar disorder is not so much that we are going to fix the genes but rather that we are going to use the genes to shed light on the biology. And then once we figure that out, we might be able to come up with ways to fix the biological pathway in which that gene participates.

Patricia:

Do our genes change over the course of our lives?

Dr. McMahon:

The actual spelling of genes, the sequence of nucleotides, of As, Cs, Ts and Gs that are known to encode proteins by and large don't change. But we are learning increasingly that there are other modifications in the genome that may play a role in how genes are turned on and off, and they are quite dynamic over time in ways that were quite surprising when they were first discovered.

The other interesting thing is that some of those changes can actually be passed on to subsequent generations. This is a field known as epigenetics, and it's one that's being very actively investigated particularly in the realm of cancer genetics nowadays.

Patricia:

Does this affect mental illness in any way?

Dr. McMahon:

Well, so far, we have no direct evidence of that, but there are intriguing indirect studies that imply that some of these processes may be involved. For example, there are some studies in mice that show that stressful life experiences can lead to modifications in sequences that regulate stress-related genes and that those modifications then can actually be passed off to the offspring of those mice that have had stressful life experiences and that they can then be undone by a different life experience in the offspring.

Patricia:

So if someone experiences emotional or physical trauma in their lifetime, particularly in childhood, what kind of effect would that have on the brain?

Dr. McMahon:

Well, we don't know very well right now what it does at the genetic level. Most of what we know comes really from studies of laboratory animals rather than human beings. But we do know from imaging studies and biochemical studies that there can be very lasting changes both in the structure and function of the brain as a result of those kinds of life experiences, and those are the same kinds of experiences that seem to predispose to a whole range of mood and anxiety problems. So what we are thinking of is that maybe what we are seeing here is that someone might be born with a genetic vulnerability, and then they experience certain kinds of key stresses in their lives that fit that vulnerability like a lock to a key, and the result of that is a psychiatric illness.

Patricia:

Does an emotional trauma or chronic stress actually alter genes?

Dr. McMahon:

It can. It can affect what genes are turned on and what genes are turned off. One area that is very actively investigated nowadays are these genes that are known to maintain the health of neurons. We used to think that once the brain finished developing, sometime in late adolescence, that it didn't change much after that, that you had sort of a fixed number of brain cells and the way in which those brain cells were connected to each other structurally didn't change much. Now we know that that's certainly not true, that both the structural connections between the brain cells and, most importantly, the number of brain cells actually changes over time.

Patricia:

Fascinating.

Dr. McMahon:

And stressful life experiences can influence that, usually in negative ways so that the replacement of neurons in certain regions of the brain can be reduced by those stresses, and also the ways in which those neurons connect to other neurons can be reduced. This is an area that's quite interesting because in animal models it's been shown that anti-depressant medications, lithium and electroconvulsive therapy, all act in ways that reverse the effects of chronic stress on the brain's structure, and so it's thought that maybe this is one of the ways in which these treatments work to alleviate depression.

Patricia:

And what role does a person's environment play in causing something like bipolar disorder?

Dr. McMahon:

Well, we know that environment plays some role, about 20 percent of the whole story, based on the twin studies, but we don't have a clear idea of what key environmental events are involved. Negative life events, stressful life experiences, trauma, all seem to be involved. It only stands to reason that they would be involved, but it's been very difficult to pinpoint specifically what's going on. This is another way that genetic findings may help us because if we are able to identify a set of important risk factors at the genetic level, it may actually be possible for us to study people who carry several of those genetic risk factors but haven't developed the illness and compare their life histories to the life history of the people who develop the illness maybe with fewer genetic risk factors.

And then we might even be able to say what specifically was different about those people who developed the illness maybe early in life with a lower genetic risk than those who didn't develop the illness even though they had a high genetic probability of having it. That's the kind of thing that might even allow us down the road to talk about preventive strategies for people who are at high risk for the illness in the same way that we focused so heavily on preventive strategies for people who are at high risk for cardiovascular disease.

Patricia:

I have read an article that suggested mental illness like bipolar disorder may have had a purpose in human evolution. Explain how this might be possible.

Dr. McMahon:

Well, this is a theory that's been around for a while, and it's triggered by the observation that mental illnesses are actually very common. Bipolar disorder probably affects between 1 and 2 percent of the population, similar rate for schizophrenia. Depression might be 10 times more common. So it seems reasonable to ask what maintains these illnesses with such high frequency in the population since they are certainly not advantageous to be ill with depression or bipolar disorder or schizophrenia. And one of the theories has been that maybe at a different times in human history certain of the genes that contribute to the risk for these illnesses actually were advantageous because perhaps they promoted creativity or willingness to explore new environments, to explore new resources, things that 10,000 years ago when the human species consisted of tiny bands of people living in pockets around world might have played a role in promoting survival. We don't have direct evidence of this.

The best analogy we have, though, comes from the genetics of diabetes, particularly type II diabetes, which as you may know has become tremendously much more common in the last 50 years than it had been before. And the theory there is that maybe some of the same genes that 10,000 years ago promoted survival by allowing individuals to make maximum use of scarce nutritional resources then become vulnerability factors for obesity and diabetes when nutrition is now not a scarce resource at all, but actually a surfeit. When we have fast food restaurants on every corner and we rarely exercise, then if we carry genes that make us very efficient metabolizers of the calories that we do ingest, that may actually work to our disadvantage.

Patricia:

So specifically, people held onto the obesity gene, which helped individuals make the most of their available food ensuring their survival. But now that we really don't need to ensure our survival through obesity, it's become an issue.

Dr. McMahon:

Exactly.

Patricia:

Okay.

Dr. McMahon:

And so we could speculate about a similar kind of thing happening for some of the genes that contribute to bipolar disorder.

Patricia:

Okay. But once the purpose of mental illness is no longer necessary for human survival, why didn't nature just select these genes out? Why is it still with us?

Dr. McMahon:

Yeah. There isn't a clear answer to that except that the fact that there are many genes that contribute a little bit to the risk of the illness might be a sufficient explanation. Nature would have a hard time eliminating those kinds of genes from the population because many people who carry them never get ill.

Patricia:

Okay.

Dr. McMahon:

On the other hand, the human population has been in a period of rapid expansion since the last Ice Age, so it's likely that there actually hasn't been a lot of natural selection acting on our species.

Patricia:

Oh, we are just getting good at surviving.

Dr. McMahon:

We are very good at surviving and very good at reproducing so that even forms of genes that might be mildly disadvantageous in an unfavorable situation persist just by the simple fact that we all have lots of kids and those kids have lots of kids.

Patricia:

Before we get to our e-mail and phone questions, doctor, you are working on a study. Can you tell us a little bit about what you are working on these days?

Dr. McMahon:

Yes. We are using some of the latest genetic technologies to try to tap at both the common and the rare genetic causes of bipolar disorder. And in order to do this, we are asking people to participate who might be from families where several people have bipolar disorder, the larger the family the better. We are hoping that these kinds of families who are often very special, meaning that they have many people with the illness, might give us some insights into some of the more rare genetic causes of the illness.

At the same time, we are also studying individuals who have developed bipolar disorder maybe early in life, particularly those who developed it in adolescence but who don't have relatives with the illness, because these kinds of folks might actually have new genetic changes, maybe these kinds of deletions and duplications that we talked about earlier. And, again, they may give us some unique insights into what causes this illness in the general population.

Patricia:

How can our listeners reach you?

Dr. McMahon:

Wow. We would be delighted if someone is interested in learning about our studies or volunteering, they can call us. Our number is 1-866-NIH-GENES, or they can e-mail either me or our study coordinator Diane Kasuba at the NIMH for more information.

Patricia:

Okay. We have a lot of e-mail questions, so let's start from North Myrtle Beach, South Carolina, "If no one else has bipolar disorder in my family, why am I the first? Is it for certain I will pass it on to my own children? When are the shock treatments recommended, and are there any bipolar meds that can affect the liver?" There are lots of questions in there.

Dr. McMahon:

Okay. Well, let me see if I can take them in order. The question why am I the first in my family to have it, that really gets very closely at what we were just talking about a moment ago, that it does seem that there are individuals, it's not common, but it's also not terribly rare, who seem to develop bipolar disorder out of the blue. They are the first person in their family to have it. We don't know the reason for that, but one of the theories is that maybe there has been a genetic error that has occurred that predisposes to the illness in that person. Or perhaps a tiny segment of the chromosome has been deleted or duplicated as part of the natural developmental process, and that that somehow has led to the illness. So we are very interested in studying folks like that because they may give us some unique insights into what causes this illness.

Now, the other questions were when are shock treatments indicated? Electroconvulsive therapy or shock treatments have been used for people with mood disorders for close to 50 years. And over that period of time, the methods for administering the treatment have gotten much more refined so that the side effects are much less, but it's still a fairly major procedure and usually requires someone to undergo a general anesthesia in a hospital setting, and the side effects are sometimes significant in terms of short-term memory loss.

At the same time, electroconvulsive therapy can be a life-saving treatment for people with depression that have failed to respond to other kinds of treatment. So it's still a very commonly administered treatment throughout the United States and Europe today.

Patricia:

And what about this listener's concerns about passing bipolar on to her children?

Dr. McMahon:

Yes. Well, we know that about 15 percent of people with bipolar disorder have bipolar disorder in their close relatives so that there is an increased risk of the illness being passed on, but it's not a dramatically increased risk compared to what might occur in the general population. I always advise people that they shouldn't worry too much about passing the illness on because probably 85 percent of the time they won't. But at the same time if you have a parent with the illness, or you are a parent with the illness, and you are watching your kids grow up, have a little higher level of suspicion if you see problems with behavioral or social withdrawal, drug abuse, things that sometimes can be a sign of an underlying mood problem. And get help a little sooner than you might otherwise do because we know that the biggest problems with mood disorders like depression and bipolar disorder in this country nowadays is that people don't get into treatment early enough, or they don't get treatment at all.

There are some medications that can cause bipolar-like symptoms, and probably the most widely studied are the steroid drugs that are sometimes given for a variety of severe illnesses. They can trigger episodes of depression and even episodes of mania. But interestingly that seems to be something that occurs in people who are already vulnerable to the illness in most cases. So this gets at this underlying cause idea that maybe something about the stress pathways which the steroid hormones are known to interact with may be involved. But also a variety of other hormones can provoke depression symptoms. There are also stimulant medications that are sometimes given that can either interfere with sleep and so predispose someone to having an episode or can directly bring on manic episodes. These are all rather uncommon, but they can occur. Anti-malaria medications sometimes can provoke mood symptoms and a variety of other things.

The best advice there is that if you are concerned about that risk, talk about it with your doctor before you start the medication. Read those package inserts that come with your prescriptions because many of them will have warnings that people with pre-existing history of depression or bipolar disorder either shouldn't take the medication at all or should take it with great care.

Well, what really determines when someone falls ill with these illnesses isn't well-understood. We know that about 80 percent of everybody who will ever develop bipolar disorder does so by their early 20s. But new cases of bipolar disorder going on well into the 40s are not rare, and we occasionally see people whose first manic episode occurs in their 50s or 60s. Now, we think that people whose bipolar disorder occurs very late in life might actually have the illness for a different reason than people who have it earlier in life.

Patricia:

Like what?

Dr. McMahon:

Well, as the brain ages, a variety of things change. There is increasing risk of cardiovascular problems, strokes, things of that nature that might go undetected except that they can provoke psychiatric symptoms.

Patricia:

Alzheimer's, does that factor in there as well?

Dr. McMahon:

Alzheimer's disease and a variety of other illnesses of the aging brain can sometimes present with symptoms that at first look a lot like depression. So it's very important, particularly in older people, that those kinds of symptoms get carefully evaluated from both a neurological and a psychiatric perspective because sometimes the underlying condition is neurological in nature. Now, I hasten to say, though, even in that case the treatment is still basically the same. So anti-depressants are still the preferred treatment for depression that occurs in people without neurological disease and in people who have depression in the context of Parkinson's or Alzheimer's or other kinds of strokes, things of that nature. But the illness seems to be similar in terms of what helps it even when the causes are different.

Patricia:

All right. We have an e-mail from Eau Claire, Wisconsin, "To what degree does disease progress as you age?"

Dr. McMahon:

Yes. That's something that has probably not been sufficiently studied in bipolar disorder. As I said, it's an illness that tends to start in adolescence or early adulthood and if left untreated will generally get more severe. We know that based on studies that were done in the era before effective treatments were available. But in the present era where there are so many good choices in terms of mood stabilizers, anti-depressants, anti-psychotics, the majority of people don't have a progression of their illness. But many do have persistent symptoms that can interfere with both their work and their social lives even when they are not severely ill.

So I think the bottom line here is that we don't yet have a way to cure the illness, and too many people tend to have persistent symptoms from the illness even when they are adequately treated. This tells us that we need better ways of controlling the underlying disease.

Patricia:

We have an e-mail from Smithtown, New York now, "What percentage of people with bipolar would you say don't have a genetic link, predisposition or emotional trauma as a link factor?"

Dr. McMahon:

Well, we don't have good data on that. The best estimate comes from epidemiologic studies where we asked people with the illness how often they had relatives who have the disorder. And one of the things we know about bipolar disorder is it can take different forms in different people. So that if we studied people with bipolar disorder and looked at their parents and siblings, we find that there is an increased risk of bipolar disorder but also a higher rate of major depression, panic disorder, alcoholism, making us wonder whether some of the same underlying familial factors can express themselves in different ways in different people.

Now, if we think of it that way, the vast majority of the people with bipolar disorder have one of those illnesses among their close relatives. If we think of it in the narrow way of saying bipolar disorder in a patient and bipolar disorder in their siblings or parents, the number is probably on the order of 10 to 15 percent. So in that narrow definition then, the majority of people with bipolar disorder would not have a positive family history. But my best guess, and I think this is probably true of many people who study bipolar disorder as I do, is that that's too narrow a view and that these are the kinds of genes that can express themselves in a variety of ways and that it would be unwise to ignore a major depression or panic disorder or other kinds of illnesses among the relatives.

Patricia:

Dayton, Ohio writes in, "Can we expect that my son who has Asperger's will also develop a bipolar condition like his father? We have organized New Horizons Bipolar Support Group."

Dr. McMahon:

Yes. Asperger's syndrome is one of these illnesses that's thought to be primarily related to autism, so it's a developmental cognitive and language disorder. It doesn't bear any known familial relationship to bipolar disorder, meaning that if you look among the relatives of people with bipolar disorder, you don't see more Asperger's, you don't see more autism, but at the same time there certainly are people who can have both illnesses.

In this case, if your son's father has bipolar disorder himself, then there is a somewhat increased risk that he could pass that predisposition on. But as I say it's not a dramatically increased risk, and I would think that most people would think that the Asperger's needs to be treated unto itself and that there should be a somewhat higher index of suspicion if there are unusual symptoms or symptoms that might be suggestive of depression or bipolar disorder.

Patricia:

New London, New Hampshire writes in, "My husband refuses to address his bipolar situation. His response is always, "Prove it, that I have it." You can't. He has been diagnosed five times by different doctors by his symptoms. Can you prove that a person is bipolar other than his behavior?"

Dr. McMahon:

I share the listener's frustration. We often find people we really think we could help if we could only help them understand that they have got this illness. And this is one of the perplexing things about psychiatric disorders, in general, is that it's often hardest for the people who have them to recognize that they have it. It's easy for any of us to recognize if we have a physical illness that it's there, but often with psychiatric illnesses that's not the case. And for the reasons that I have talked about, you really can't prove that somebody has bipolar disorder even if they have the full set of genetic risk factors. That just tells you that they might be more likely to have the illness. It doesn't prove that they have it. There is no imaging test that can be done. There is no blood test that can be done to prove that someone has the illness.

So I always encourage people who have a loved one who they think is ill is not give up. Just let your loved one know that you are there to help, that you will really try to get them the care they need but that fundamentally they have to be willing to go along with what the doctors are recommending.

Patricia:

Now, the second part to this question is that this person's doctor is administering testosterone shots, and the concern is that that might elevate his condition of mania.

Dr. McMahon:

Well, as I mentioned earlier, it's true that hormone treatments can certainly contribute to manic and depressive symptoms in people who are otherwise predisposed to the illness. So if I were the doctor prescribing this testosterone, I would want to hear from my patient's spouse that she thinks it's making the situation worse because I may very well want to make adjustments on that basis.

Patricia:

We have an e-mail from Indiana, "What effect does menopause have on bipolar disorder or vice versa?"

Dr. McMahon:

Yes. Menopause has a huge impact on the underlying hormonal biology of a woman, and in the same way that externally administered hormones can affect bipolar disorder, natural hormonal changes that come with menopause can as well. The traditional teaching has been that the rule of threes applies, that after menopause about one-third of people with bipolar disorder will be experience an improvement in their symptoms, about one-third will worsen, and about one-third will stay the same. But I think that just tells us that gee, we really don't understand this at the level we need to, and that there probably are forms of bipolar disorder that actually do get distinctly better after menopause. Maybe these are forms of the illness that are driven by the hormonal changes in a younger woman but that there clearly also are forms that get worse after menopause, and we need to understand why that is.

Patricia:

All right. Doctor, we are almost out of time. But before we go, quickly tell us one more time about your study, recap your study, and leave our listeners with some thoughts.

Dr. McMahon:

Certainly. Well, the main thing I want to leave people with is that they should never give up hope. We really are now at a time of unprecedented discoveries in this field. Almost every week, something fundamentally new is discovered, and I am really very hopeful that that's going to lead to some new treatments in the near future.

We do encourage people if they have the illness, particularly if they belong to large family where several people have bipolar disorder, to give us a call and talk with us about participating in our study. It's really easy to do. You don't have to travel to Bethesda. We can deal with everything over the telephone. And it's a way of really contributing to the kind of medical progress we need to lick this disorder in future generations. The number again is 1-866-NIH-GENES or you can e-mail us, and we will be happy to provide you with the information.

Patricia:

Thank you so much, Dr. McMahon, and thank you to the audience for joining us tonight.